Crystals of hydroxynorephedrine derivative

ABSTRACT

The present invention provides ethyl (−)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-2,5-dimethylphenoxy]acetate hydrochloride, crystalline forms thereof and pharmaceutical compositions containing them, which have excellent β 3 -adrenoceptor stimulating effects, therapeutic effects on pollakiuria or urinary incontinence and storage stabilities and are useful as a medicament.

TECHNICAL FIELD

The present invention relates to ethyl(−)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-2,5-dimethylphenoxy]acetatehydrochloride and in particular crystalline forms thereof, which haveβ₃-adrenoceptor stimulating effects and are useful as a medicament forthe treatment of pollakiuria or urinary incontinence.

BACKGROUND ART

Ethyl (−)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-2,5-dimethylphenoxy]acetate represented by formula (II):

has been disclosed in WO00/02846 by the present applicant and is itselfa known compound. This compound has been known to have an excellentβ₃-adrenoceptor stimulating effect and is useful as a medicament for thetreatment of pollakiuria or urinary incontinence.

Compound (II) exhibits excellent therapeutic activities for thetreatment of pollakiuria or urinary incontinence, while it could havebeen produced only in amorphous forms by the preparation method asdescribed in WO00/02846. For producing the amorphous compound (II) in asubstantially pure form, troublesome purification steps have beenrequired. Compound (II) is difficult to formulate into solid formpreparations due to its viscous physical property. Moreover, compound(II) has unsatisfactory stability, and when stored under ordinaryconditions for a long period, it has serious problems to discolor anddecrease the content of the active ingredient. Accordingly, there is aneed for a novel form of compound (II) which has satisfactory storagestability and is usable as a drug substance.

DISCLOSURE OF THE INVENTION

The present inventors had intensively investigated various acid additionsalts of compound (II), and found unexpectedly that a hydrochloride saltof compound (II), that is ethyl(−)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methyethyl]amino]ethyl]-2,5-dimethyl-phenoxy]acetate hydrochloride represented byformula (I):

can be obtained in the form of highly crystalline solid. Moreover, thepresent inventors had investigated crystals of compound (I), and foundthat crystals of the present invention have surprisingly excellentstorage stabilities and are useful for a drug substance. Based on thesefindings, the present invention has been accomplished.

The present invention therefore provides:

-   (1) a compound represented by formula (I):

-   (2) a crystal of a compound according to the above (1);-   (3) the crystal according to the above (2) which shows an X-ray    powder diffraction pattern having characteristic peaks at a    diffraction angle (2θ±0.1 degree) of 8.9, 10.2, 12.9, 14.2, 15.6,    18.4 and 20.6 degrees (hereinafter, referred to as “crystalline form    A”);-   (4) the crystal according to the above (2) which shows an X-ray    powder diffraction pattern having characteristic peaks at a    diffraction angle (2θ±0.1 degree) of 7.3, 10.1, 12.2, 14.6, 15.9,    16.0, 18.7 and 21.8 degrees (hereinafter, referred to as    “crystalline form B”);-   (5) a pharmaceutical composition which comprises, as an active    ingredient, a compound according to any one of the above (1) to (4);-   (6) the pharmaceutical composition according to the above (5), for    the treatment of pollakiuria or urinary incontinence;-   (7) a medicament for treating pollakiuria or urinary incontinence,    which comprises, as an active ingredient, a compound according to    any one of the above (1) to (4);-   (8) a use of a compound according to any one of the above (1) to    (4), for the manufacture of a medicament for treating pollakiuria or    urinary incontinence; and-   (9) a method for treating pollakiuria or urinary incontinence, which    comprises administering a therapeutically effective amount of a    compound according to any one of the above (1) to (4).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an X-ray powder diffraction pattern of crystalline form A ofcompound (I) obtained in Example 2 where the ordinate shows the X-rayintensity in cps and the abscissa shows the diffraction angle in 2θ.

FIG. 2 is an X-ray powder diffraction pattern of crystalline form B ofcompound (I) obtained in Example 3 where the ordinate shows the X-rayintensity in cps and the abscissa shows the diffraction angle in 2θ.

BEST MODE FOR CARRYING OUT THE INVENTION

A compound represented by formula (I) of the present invention, and theparticular crystalline forms A and B thereof can be produced as follows.

Compound (II), which is used as the starting material of the presentinvention, can be prepared in amorphous forms by the known procedure asdescribed in WO00/02846.

Compound (I) can be obtained in crystalline forms by reacting a solutionof compound (II) in an appropriate organic solvent, with hydrochloricacid or hydrogen chloride.

Examples of the organic solvent employed in the above reaction includeethanol, carboxylic acid esters such as ethyl acetate and the like,hydrocarbons such as toluene and the like, acetonitrile and the like.The organic solvents can be used either singly or as a mixture of two ormore solvents.

The source of HCl can be used in the form of hydrochloric acid, or asolution of the above organic solvent into which gaseous hydrogenchloride is blown.

The reaction of compound (II) with hydrochloric acid or hydrogenchloride takes place immediately. The time required for crystallizationvaries depending upon crystallization conditions such as the amounts oforganic solvents and HCl employed, as well as the crystallizationtemperature and the like, and it takes ordinarily about 1 to 24 hours.Preferably, the crystallization is carried out by stirring the reactionmixture at a temperature of about 0 to about 30° C. for 1 to 6 hours toprovide compound (I).

Recrystallization of compound (I) thus obtained, from a suitable solventprovides crystalline forms A and B, which are the particular crystallineforms of compound (I) of the present invention.

For example, crystalline form A can be obtained as follows. Compound (I)is dissolved in ethanol under heating, and to the resulting solution isadded, if necessary, t-butyl methyl ether, isopropanol or water at atemperature of about 40 to about 50° C. with stirring, then the mixtureis stirred at a temperature of about 40 to about 50° C. for 1 to 6hours. Thereafter, the mixture is stirred at a temperature of about 0 toabout 30° C. for another 1 to 6 hours to provide crystalline form A.

Crystalline form B can be obtained as follows. Compound (I) is dissolvedin ethanol and tetrahydrofuran under heating, and to the resultingmixture is added additional tetrahydrofuran at about 40° C. withstirring. The mixture is stirred at a temperature of about 0 to about10° C. for 1 to 12 hours to provide crystalline form B.

The crystalline forms A and B of compound (I) thus obtained can beidentified by their characteristic diffraction peaks as shown in theX-ray powder diffraction charts of FIGS. 1 and 2:

-   (1) crystalline form A has characteristic peaks at a diffraction    angle (2θ±0.1 degree) of 8.9, 10.2, 12.9, 14.2, 15.6, 18.4 and 20.6    degrees as shown in FIG. 1; and-   (2) crystalline form B has characteristic peaks at a diffraction    angle (2θ±0.1 degree) of 7.3, 10.1, 12.2, 14.6, 15.9, 16.0, 18.7 and    21.8 degrees as shown in FIG. 2.

The crystalline forms A and B of compound (I) can be stored atordinarily storage conditions such as 25° C., 60% relative humidity andthe like for a long period without changing their crystalline forms, andare also chemically stable. The crystalline forms A and B have excellentflowabilities and good handling properties, and are suitable forformulation.

The compound represented by formula (I) of the present inventionexhibits an excellent β₃-adrenoceptor stimulating effect and relaxesbladder detrusor muscle as well as increases the volume of bladder.Therefore, compound (I) of the present invention can be used for thetreatment of dysuria such as pollakiuria, urinary incontinence in thecase of nervous pollakiuria, neurogenic bladder dysfunction, nocturia,unstable bladder, cystospasm, chronic or acute cystitis, chronic oracute prostatitis, prostatic hypertrophy and the like, idiopathicpollakiuria, idiopathic urinary incontinence and the like.

The compound represented by formula (I) of the present invention can beused, if required, in combination with another medicament for thetreatment of dysuria. Examples of such a medicament includeanticholinergic agents such as oxybutynin hydrochloride, propiverinehydrochloride, tolterodine, darifenacin, fesoterodine, trospiumchloride, KRP-197, YM-905 and the like; smooth muscle relaxants such asflavoxate hydrochloride and the like; β₂-adrenoceptor agonists such asclenbuterol hydrochloride, formoterol fumarate and the like;α₁-adrenoceptor agonists such as midodrine hydrochloride, R-450,GW-515524, ABT-866 and the like; estrogen preparations such asconjugated estrogen, estriol, estradiol and the like; central nervoussystem agents such as antiepileptic agents, antidepressants and the likesuch as imipramine, reserpine, diazepam, carbamazepine and the like;neurokinin receptor antagonists such as TAK-637, SB-223956, AZD-5106 andthe like; potassium channel openers such as KW-7158, AZD-0947, NS-8,ABT-598, WAY-151616 and the like; vanilloid receptor agonists such ascapsaicin, resiniferatoxin and the like; vasopressin 2 receptor agonistssuch as desmopressin, OPC-51803, WAY-141608 and the like;α₁-adrenoceptor antagonists such as tamsulosin, urapidil, naftopidil,silodsin, terazosin, prazosin, alfuzosin, fiduxosin, AIO-8507L and thelike; GABA receptor agonists such as baclofen and the like; serotoninreceptor antagonists such as REC-15-3079 and the like; dopamine receptoragonists such as L-dopa and the like, or dopamine receptor antagonists;antiallergic agents such as histamine receptor antagonists such assulplatast tosilate, norastemizole and the like; NO synthase inhibitorssuch as nitroflurbiprofen and the like.

In the case of using a pharmaceutical composition comprising thecompound represented by formula (I) or the crystalline forms thereof fora medical treatment, various dosage forms can be administered dependingupon their usages. Exemplary dosage forms include powders, granules,fine granules, dry syrups, tablets, capsules, injections, liquids,ointments, suppositories, poultices and the like, which are administeredorally or parenterally.

Pharmaceutical compositions can be formulated by admixing, diluting ordissolving with appropriate pharmaceutical additives such as excipients,disintegrators, binders, lubricants, diluents, buffers, isotonic agents,preservatives, wetting agents, emulsifying agents, dispersing agents,stabilizing agents, solubilizing agents and the like, according to aconventional formulation procedure depending upon their dosage forms.

In the case of using a pharmaceutical composition of the presentinvention for a medical treatment, the dosage of the compoundrepresented by formula (I) or the crystalline forms thereof isappropriately determined depending on the age, sex or body weight of theindividual patient, the severity of the disease, the condition to betreated and the like. A typical dosage for oral administration is in therange of from about 0.01 mg to about 100 mg per day per adult human. Atypical dosage for parenteral administration is in the range of fromabout 0.0003 mg to about 30 mg per day per adult human. The dosages maybe administered in single or divided doses of one to several timesdaily.

Where the compound represented by formula (I) or the crystalline formsthereof is used in combination with another medicament for the treatmentof dysuria, pharmaceutical compositions can be formulated by admixingseparately each of active ingredients, or admixing concurrently both ofactive ingredients, with pharmaceutically acceptable additives such asexcipient, disintegrator, binder, lubricant, diluent, buffer, isotonicagent, preservative, wetting agent, emulsifying agent, dispersing agent,stabilizing agent, solubilizing agent and the like, and administeredseparately or concurrently in an oral or pareteral dosage form. Whereseparately formulated pharmaceutical compositions are used, thecompositions may be mixed together with an appropriate diluent, andadministered simultaneously. Alternatively, where separately formulatedpharmaceutical compositions are used, the compositions may beadministered separately, concurrently or at different intervals.

EXAMPLE

The following examples, reference examples and test examples illustratethe invention in further detail. It is to be understood, however, thatthey are not to be construed as limiting the scope of the invention inany way.

X-ray powder diffraction patterns of the present crystalline forms wereobtained using an X-ray diffraction analyzer, RINT1400 (Rigaku) whichwas operated at 30 kV/100 mA and using CuKα-ray beam. Melting pointswere determined using a micro melting point apparatus MP-J3(Yanagimoto). The starting material, compound (II), was preparedaccording to the procedure as described in Example 2 in WO00/02846.

Reference Example 1 Ethyl(−)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methyethyl]amino]ethyl]-2,5-dimethylphenoxy]acetate(Compound(II))

To a mixture of ethyl 2-[4-(2-bromoethyl)-2,5-dimethylphenoxy]acetate(18.1 g), (1R,2S)-p-hydroxynorephedrine (8.0 g) and N,N-dimethylforamide(45 g) was added diisopropylamine (7.26 g), and the resulting mixturewas stirred at 100° C. for 1.5 hours under a nitrogen atmosphere. Aftercooling to room temperature, ethyl acetate (140 g) and water (60 g) wereadded to the reaction mixture, and the organic layer was separated. Theaqueous layer was extracted with additional ethyl acetate (72 g). Thecombined organic layers were washed with water and brine successively,dried over sodium sulfate, and filtered. The solvent was removed underreduced pressure to afford a crude product (27.8 g). A 15 g portion ofthe crude product was purified by column chromatography using 400 g ofaminopropylsilicagel (eluent: dichloromethane/ethanol=20/1) to giveethyl(−)-2-[4-[2-[[(1S,2R)-2-hydroxy2-(4-hydroxyphenyl)-1-methyethyl]amino]ethyl]-2,5-dimethylphenoxy]acetate(4.48 g) as a colorless amorphous.

¹H-NMR(CDCl₃)δppm: 0.98 (3H, d, J=6.1 Hz), 1.33 (3H, t, J=7.0 Hz), 2.18(3H, s), 2.21 (3H, s), 2.6-3.0 (5H, m), 4.30 (2H, q, J=7.0 Hz), 4.50(1H, d, J=5.5 Hz), 4.61 (2H, s), 6.42 (1H, s), 6.69 (2H, d, J=8.5 Hz),6.78 (1H, s), 7.05 (2H, d, J=8.6 Hz)

Example 1 Ethyl(−)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methyethyl]amino]ethyl]-2,5-dimethylphenoxy]acetatehydrochloride (Compound(I))

A mixture of ethyl 2-[4-(2-bromoethyl)-2,5 -dimethyl-phenoxy]acetate (23g), (1R,2S)-p-hydroxynorephedrine (10 g), diisopropylamine (9.1 g) andN,N-dimethylforamide (56 g) was heated at 100° C. for 2 hours under anitrogen atmosphere. After cooling to room temperature, ethyl acetate(180 g) and water (75 g) were added to the reaction mixture. The organiclayer was separated, and the aqueous layer was extracted with additionalethyl acetate (90 g). The combined organic layers were washed with waterand brine, dried over sodium sulfate, and filtered. The solvent wasremoved under reduced pressure, and the residue was dissolved in toluene(38.5 g). To the resultant solution was added dropwise 30 weight percenthydrogen chloride solution in ethanol (6.1 g) under ice cooling, and theresulting mixture was stirred at room temperature for 2 hours forcrystallization. The precipitated crystals were collected by filtration,dried at 60° C. for 6 hours in vacuo to give 15 g of compound (I).¹H-NMR(DMSO-d₆)δ ppm: 0.96 (3H, d, J=6.7 Hz), 1.22 (3H, t, J=7.1 Hz),2.15 (3H, s), 2.26 (3H, s), 2.9–3.3 (5H, m), 4.16 (2H, q, J=7.1 Hz),4.76 (2H, s), 5.08 (1H, br m). 5.97 (1H, d, J=4.0 Hz), 6.68 (1H, s),6.76 (2H, d, J=8.5Hz), 6.96 (1H, s), 7.17 (2H, d, J=8.5 Hz), 8.91 (2H,br s), 9.43 (1H, s)

Example 2 Crystalline form A of ethyl(−)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methyethyl]amino]ethyl]-2,5-dimethylphenoxy]acetatehydrochloride

A mixture of 17.0 g of compound (I) obtained in Example 1 and ethanol(130 g) was heated at 70° C. with stirring until it appeared to be aclear solution. After insoluble materials were filtered off, thefiltrate was cooled to 40° C., and seed crystals were added thereto. Themixture was stirred at 40° C. for 1.5 hours for crystallization, andt-butyl methyl ether (68 g) was added. After the resulting mixture wasstirred for 1 hour additionally, the suspension was cooled to 20° C.,and t-butyl methyl ether (58 g) was added. The suspension was allowed tostand overnight at room temperature, and then stirred for 3 hours underice cooling. The precipitated crystals were collected by filtration, anddried at 60° C. overnight in vacuo to give 13.0 g of crystals. Meltingpoint: 194–196° C.

The crystals were identified as crystalline form A by an X-ray powderdiffraction analysis. An X-ray powder diffraction pattern was shown inFIG. 1.

Example 3 Crystalline form B of ethyl(−)-2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methyethyl]amino]ethyl]-2,5-dimethylphenoxy]acetatehydrochloride

A mixture of 100 mg of compound (I) obtained in Example 1 and ethanol(245 μL) and tetrahydrofuran (45 μL) was heated at 75° C. with stirringuntil it appeared to be a clear solution. The solution was cooled to 40°C., and tetrahydrofuran (1.6 mL) was added. The resulting mixture wasimmediately cooled with ice bath, and stirring was continued for 7hours. The mixture was allowed to stand overnight at room temperature,and then stirred for 2 hours under ice cooling. The precipitatedcrystals were collected by filtration, and dried at 60° C. overnight invacuo to give 60.5 mg of crystals. Melting point: 177–179° C.

The crystals were identified as crystalline form B by an X-ray powderdiffraction analysis. An X-ray powder diffraction pattern was shown inFIG. 2.

Stability Test

Stability test was carried out under a condition of storage at 60° C.for crystalline form A obtained in Example 2, crystalline form Bobtained in Example 3 and the amorphous form of compound (II) obtainedin Reference Example 1. The residual percentage of test substances wasdetermined by HPLC, and the changes in appearance were observed.

TABLE 1 Example 2 Example 3 Reference Storage Crystalline form ACrystalline form B example 1 Period Initial 7 days Initial 7 daysInitial 7 days Residual 100 100 100 99.9 100 40.0 percentage Appear-white white white white Color- tannish ance less

The results are shown in the above table 1. Crystalline forms A and B ofthe present invention indicate no changes in appearance and haveexcellent storage stabilities as compared with the amorphous compound(II).

INDUSTRIAL APPLICABILITY

The compound represented by formula (I) of the present invention has anexcellent β₃-adrenoceptor stimulating effect and therapeutic effect onpollakiuria or urinary incontinence, and is useful as a medicament. Thecompound represented by formula (I) of the present invention has ahighly crystalline property and can be obtained in high purity by aconvenient purification procedure, and therefore is suitable forcommercial production. Moreover, the particular crystalline forms A andB of the present invention have excellent storage stabilities,flowabilities and handling properties, and are suitable for formulation.

1. A crystalline compound represented by formula (I):

which shows an X-ray powder diffraction pattern having characteristicpeaks at a diffraction antic (2θ±0.1 degree) of 8.9, 10.2, 12.9, 14.2,15.6, 18.4 and 20.6 degrees.
 2. A crystalline compound representedformula (I):

which shows an X-ray powder diffraction pattern having characteristicpeaks at a diffraction angle (2θ±0.1 degree) of 7.3, 10.1, 12.2, 14.6,15.9, 16.0, 18.7 and 21.8 degrees.
 3. A pharmaceutical composition whichcomprises, as an active ingredient, a crystalline compound according toclaim
 1. 4. A pharmaceutical composition which comprises, as an activeingredient, a crystalline compound according to claim
 2. 5. Thepharmaceutical composition according to claim 3, for the treatment ofpollakiuria or urinary incontinence.
 6. The pharmaceutical compositionaccording to claim 4, for the treatment of pollakiuria or urinaryincontinence.
 7. A medicament for treating pollakiuria or urinaryincontinence, which comprises, as an active ingredient, a crystallinecompound according to claim
 1. 8. A medicament for treating pollakiuriaor urinary incontinence, which comprises, as an active ingredient, acrystalline compound according to claim
 2. 9. A method for treatingpollakiuria or urinary incontinence, which comprises administering atherapeutically effective amount of a crystalline compound according toclaim
 1. 10. A method for treating pollakiuria or urinary incontinence,which comprises administering a therapeutically effective amount of acrystalline compound according to claim 2.